The microbial community in the human gastrointestinal (GI) tract is a key factor to the health and nutrition of its host (1). Loss of the fragile equilibrium within this complex ecosystem, termed dysbiosis, is involved in numerous pathologies; amongst them are the inflammatory bowel diseases (IBD). IBD incidence rose during the 20th century and will continue to increase substantially, strongly affecting individuals in the most challenging and productive years of life (2). IBD develop at the intersection of genetic predisposition, dysbiosis of the gut microbiota and environmental influences (3).
Caspase recruitment domain 9 (CARD9), one of the numerous IBD susceptibility genes, codes for an adaptor protein integrating signals downstream of pattern recognition receptors. It is particularly involved in response toward fungi via C-type lectins sensing (4,5). Card9 has been shown to mediate colitis recovery via interleukin 22 (IL22) pathway activation and CARD9 knockout (Card9−/−) mice have enhanced susceptibility to colitis and increased load of intestinal fungi (6). Dysbiosis is often seen as an actor of intestinal inflammation via the increase level of pro-inflammatory microorganisms such as Proteobacteria (7). However, the lack of microorganisms with regulatory effects might also enhance inflammation (8,9).
Accordingly, there is a need to develop new drugs that will be suitable for preventing or treating inflammatory bowel diseases (IBD). In this way, it has been suggested that characterization of new compounds for treatment of IBD may be highly desirable.
In the present invention, the inventors used C57BL/6 wild-type (WT), Card9−/− and germ-free (GF) mice to study the role of the intestinal microbiota in the impaired recovery of Card9−/− mice after colitis. The inventors found that CARD9 deletion had a dramatic effect on both bacterial and fungal gut microbiota. Moreover, the transfer of Card9−/− microbiota into WT GF recipient was sufficient to recapitulate the defective IL22 activation as well as the increased sensitivity to colitis observed in Card9−/− mice. This defect was explained by the inability of the Card9−/− microbiota to metabolize tryptophan into aryl hydrocarbon receptor (AhR) ligands. Indeed, recent data suggest that tryptophan catabolites from microbiota have a role in mucosal immune response via AhR (10) which in turns modulates IL22 production, a cytokine with well-known effects on intestinal homeostasis (10,11). In human comparable mechanisms seems involved, since the inventors showed that IBD patients' microbiota exhibit an impaired production of AhR ligands that correlates with Card9 genotype.
There is no disclosure in the art of the use of AhR agonist in the prevention or treatment of IBD with abnormal microbiota exhibiting an impaired production of AhR ligands, nor the use of bacteria exhibiting AhR activation properties in the prevention or treatment of IBD with abnormal microbiota exhibiting an impaired production of AhR ligands.